Numerous studies have reported the effects of EPO administration to a wide range of species. Recombinant EPO administration induces polycythemia in a dose-related manner; summaries of these early preclinical studies are found in several comprehensive reviews (90,91). Mice have also been used for comparative evaluations of the in vivo activity of the EPO-related moiety darbepoietin alfa, an EPO derivative with a modified polypeptide and glycosylation structure (reviewed in ref. 92), and to demonstrate the activity of small-molecule EPO mimetics (93). rHuEPO has a wide cross-species activity that apparently extends from mammals to fish (94). Collectively, these studies indicate that in many species, EPO is a potent and highly specific stimulant of erythropoiesis.

A transgene including 0.4 kb of endogenous 5' untranslated sequences flanking the 5 exons of the human genomic EPO gene sequences resulted in high serum EPO

Table 7

Genetic Models of Chronic Elevation of Hematopoietic Growth Factor Amounts in Mice

Factor Genetic basis of model Reference

EPO Transgenesis 95

EPO Reconstitution with hematopoietic cells infected with EPO-expressing 98 recombinant retrovirus

G-CSF Reconstitution with hematopoietic cells infected with G-CSF-expressing 104 recombinant retrovirus

GM-CSF Transgenesis 107

GM-CSF Reconstitution with hematopoietic cells infected with GM-CSF-expressing 111 recombinant retrovirus

IL-11 Transgenesis 117

IL-11 Reconstitution with hematopoietic cells infected with IL-11-expressing 115

recombinant retrovirus 114

Abbreviations: EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin.

concentrations and sustained polycythemia in mice (95). Subsequent transgenic studies exploited the transcriptional activity of this short EPO promoter fragment to identify more distant but contiguous regulatory elements that together regulate EPO expression in liver and kidney and in response to hypoxia (96,97). Murine reconstitution experiments using marrow cells over-expressing monkey EPO resulted in a severe, progressive, and ultimately fatal polycythemia with marked expansion of erythropoiesis (98).

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